WO2015153379A1 - Formulations de posologie fixe d'inhibiteur d'enzyme de conversion de l'angiotensine (ace) et de chlorthalidone diurétique - Google Patents

Formulations de posologie fixe d'inhibiteur d'enzyme de conversion de l'angiotensine (ace) et de chlorthalidone diurétique Download PDF

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Publication number
WO2015153379A1
WO2015153379A1 PCT/US2015/023193 US2015023193W WO2015153379A1 WO 2015153379 A1 WO2015153379 A1 WO 2015153379A1 US 2015023193 W US2015023193 W US 2015023193W WO 2015153379 A1 WO2015153379 A1 WO 2015153379A1
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WO
WIPO (PCT)
Prior art keywords
milligrams
chlorthalidone
lisinopril
igrams
suspension
Prior art date
Application number
PCT/US2015/023193
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English (en)
Inventor
Dorai RAJAN
Himanshu SUD
Original Assignee
Ailex Pharmaceuticals, Pvt. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Ailex Pharmaceuticals, Pvt. Ltd. filed Critical Ailex Pharmaceuticals, Pvt. Ltd.
Publication of WO2015153379A1 publication Critical patent/WO2015153379A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • This invention is directed to fixed dose pharmaceutical compositions comprising an angiotensin converting enzyme (ACE) inhibitor and a diuretic, preferably Lisinopril and Chlorthalidone, and to methods of treating hypertension using both drugs in combination.
  • ACE angiotensin converting enzyme
  • Angiotensin converting enzyme (ACE) inhibitors are considered a suitable first-step option in the treatment of hypertension in a diversity of patient types.
  • Angiotensin converting enzyme inhibitor (ACE inhibitors) drugs that are approved for the treatment of hypertension include Benazepril (Lotensin), Captopril (Capoten), Enalapril/Enalaprilat (Vasotec oral and injectable), Fosinopril (Monopril), Lisinopril (Zestril and Prinivil), Moexipril (Univasc), Perindopril (Aceon), Quinapril (Accupril), Ramipril (Altace), and Trandolapril (Mavik).
  • JNC 7 The Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), the World Health Organization / International Society of Hypertension, the European Society of Hypertension / European Society of Cardiology, and the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force currently endorse ACE inhibitors as an option for the first line therapy in patients with essential hypertension, especially in patients with a high coronary disease risk profile, diabetes with renal disease / proteinuria, heart failure, and/or a history of myocardial infarction.
  • Lisinopril is one of the most prescribed ACE inhibitors for the treatment of hypertension.
  • the compound l-(N 2 -[(S)-l-carboxy-3-phenylpropyl]-L-lysyl)-L-proline, having the generic name lisinopril, as well as therapeutically acceptable salts thereof, are described in U.S. Pat. Ser. No. 4,374,829 (Merck & Co. Inc.), incorporated herein by reference. In said patent the compound is described in Example 119, and is referred to as N- a-[l (S)-l-carboxy-3-phenylpropyl]-L-lysyl-L-proline.
  • a typical lisinopril formulation consists of lisinopril dihydrate, which can be any dose from lmg-100 mg, the fillers (diluents)-dibasic calcium phosphate dihydrate and mannitol, maize starch as a binder and disintegrant and magnesium stearate as a lubricant.
  • Dose strength of Lisinopril in FDA approved drug product ranges from 2.5 mg to 40 mg.
  • the long-acting diuretic chlorthalidone has been known for decades as an effective treatment to lower elevated arterial blood pressure (arterial hypertension or hypertension).
  • the compound received U.S. Pat. No. 3,055,904, which disclosed a dosage range of 50 mg to 200 mg orally one to three times a day or 100 mg every second day.
  • U.S. Pat. No. 5,948,799 discloses a typical range of chlorthalidone of 6.25-200 mg daily and a preferred range of 12.5 to 100 mg daily for use in the treatment of non-ischemic congestive heart failure in combination with amlodipine and/or digoxin; this patent does not address the treatment of hypertension.
  • the U.S. Food and Drug Administration's (FDA) approved starting dose for hypertension for chlorthalidone is 15 mg daily; and the marketed dose strengths are 15, 25 and 50 mg for monotherapy.
  • BP blood pressure
  • BP blood pressure
  • HCTZ hydrochlorothiazide
  • hydrochlorothiazide Despite extensive clinical experiences with chlorthalidone, hydrochlorothiazide (HCTZ) remains the more popular diuretic choice among clinicians in the context of developing single-pill antihypertensive combinations. Chlorthalidone has a longer duration of action compared with HCTZ and is a more effective antihypertensive agent over 24 hours. Because it was used in most of the US-based hypertension outcome trials, including
  • the fixed combination dosage form can be provided in the form of a syrup where the desired ratio of Angiotensin Converting Enzyme inhibitor to Chlorthalidone is provided and the patient takes the prescribed amount of syrup.
  • the syrup would be provided with appropriate flavoring agents, stabilizers, solubility agents and other excipients to form a pharmaceutically acceptable oral syrup.
  • Lisinopril In general, lower doses of Lisinopril are preferred to be co-formulated with lower doses of Chlorthalidone, and higher doses of Lisinopril tend to be more useful with higher doses of Chlorthalidone. More preferred daily doses for adults range from 2.5 mg to 100 mg of Chlorthalidone and 2.5 mg to 100 mg of Lisinopril. Most preferred daily dose for adults range from 5 mg to 50 mg of Chlorthalidone and 5 mg to 50 mg of Lisinopril.
  • the amount of Chlorthalidone and Lisinopril can be easily varied as can the amounts of the excipients with the only limitation being the need to form an acceptable tablet.
  • Example- 1 Preparation of a tri-layer 10 mg Chlorthalidone and 5 mg Lisinopril Tablet Formulation of Chlorthalidone active blend
  • Chlorthalidone active blend composition The following ingredients are used at the specified weight percentages to formulate a Chlorthalidone active blend composition; Ingredient Quantity, mg Weight %
  • Step-1 The mixture from Step-1 is placed in a suitably sized "V" blender; the remaining microcrystalline cellulose and sodium starch glycolate are then added and mixed for 15 minutes.
  • the blended mixture from Step- 3 is dry granulated on a suitable roller compactor.
  • the roller-compacted material is then milled to a particle size suitable for tablet compression.
  • the milled material from Step-4 is placed in a suitably sized "V" blender.
  • the remaining magnesium stearate is added to the blender and the material is mixed for 3 minutes to obtain the final active blend.
  • the blended mixture from Step-2 is dry granulated on a suitable roller compactor.
  • magnesium stearate is added to the blender and the material is mixed for 3 minutes to obtain the final inactive blend.
  • Step- 3 The blended mixture from Step- 3 is dry granulated on a suitable roller compactor.
  • the roller-compacted material is then milled to a particle size suitable for tablet compression.
  • magnesium stearate is added to the blender and the material is mixed for 3 minutes to obtain the final active blend.
  • Tablets can be compressed using a multi layer tablet press such as Korsch TRP 900 multi layer tablet press.
  • the inactive layer separates the Chlorthalidone layer and the Lisinopril layer.
  • all three layers are of equal weight, 150 mg each.
  • Total tablet weight is 450 mg and the tablet contains 10 mg of Chlorthalidone active and 5 mg of Lisinopril active, respectively.
  • the co-formulation of Lisinopril and Chlorthalidone as a pharmaceutically acceptable syrup is also part of the invention.
  • the liquid, orally dosable solution of Lisinopril and Chlorthalidone comprises, on a weight to weight basis, about 1 to 2 parts Lisinopril to every 1 to 4 parts Chlorthalidone, in sufficient pharmaceutically acceptable syrup, to provide a pharmaceutically acceptable dose of the Lisinopril - Chlorthalidone combination.
  • the intention is to allow a patient in need thereof to take a liquid dose of Lisinopril and
  • Chlorthalidone appropriate for the treatment in a convenient 5 to 10 ml or so amount with the absolute amount of Lisinopril and Chlorthalidone being varied so as to give the appropriate dosage of the Lisinopril and Chlorthalidone to a patient in need thereof.
  • the co-formulated syrup should be shelf stable meaning that the components of the formulation should not settle and the syrup will not lose potency or support bacterial contamination.
  • Another liquid dosage form is selected from the group consisting of: about 2 to 5 milligrams Lisinopril and about 2 to 5 milligrams Chlorthalidone in 5 milliliter suspension; about 2 to 5 milligrams Lisinopril and about 5 to 10 milligrams Chlorthalidone in 5 milliliter suspension; about 5 to 10 milligrams Lisinopril and about 10 to 15 milligrams Chlorthalidone in 5 milliliter suspension; about 10 to 15 milligrams Lisinopril and about 20 to 25 milligrams Chlorthalidone in 5 milliliter suspension; about 15 to 20 milligrams Lisinopril and about 20 to 25 milligrams Chlorthalidone in 5 milliliter suspension; about 20 to 25 milligrams Lisinopril and about 25 to 30 milligrams Chlorthalidone in 5 milliliter suspension; about 25 to 35 milligrams Lisinopril and about 30 to 40 milligrams Chlor
  • Still another liquid dosage form is selected from the group: about 5 milligrams Lisinopril and about 6.25 milligrams Chlorthalidone in 5 milliliter suspension; about 20 milligrams Lisinopril and about 12.5 milligrams Chlorthalidone in 5 milliliter suspension; about 40 milligrams Lisinopril and about 15 milligrams Chlorthalidone in 5 milliliter suspension; and about 40 milligrams Lisinopril and about 25 milligrams Chlorthalidone in 5 milliliter suspension.
  • a 5 ml suspension containing 5 mg lisinopril and 6.25 mg chlorthalidone was prepared by the following process:
  • a 5 ml suspension containing 20 mg lisinopril and 12.5 chlorthalidone was prepared by the following process:
  • a 5 ml suspension containing 40 mg lisinopril and 15 mg chlorthalidone was prepared by the following process: 400 kg sugar was dissolved in 300 liters of purified water and filtered through a 100 mesh filter into a tank. Then a citric acid buffer was prepared using 1 kg citric acid and 4.5 kg sodium citrate in 20 L purified water and added to the tank. 100 kg glycerin and 4 kg sodium carboxy methylcellulose were stirred together and added to the tank. 8.80 kg of lisinopril dihydrate USP was suspended in 20 L purified water and filtered through a 100 mesh filter into the tank.
  • a 5 ml suspension containing 40 mg lisinopril and 25 mg chlorthalidone was prepared by the following process:
  • 0.550 kg of lisinopril dihydrate USP was sifted through a 40 mesh screen, 2.000 kg of D- Mannitol was sifted through a 20 mesh screen and the lisinopril and mannitol were then blended together in a double cone blender.
  • 0.625 kg of chlorthalidone was sifted through a 40 mesh screen and 1.920 kg of dicalcium phosphate was sifted through a 20 mesh screen.
  • the chlorthalidone and dicalcium phosphate were then blended together in a double cone blender.
  • the lisinopril-mannitol mixture was then added to the chlorthalidone-dicalcium phosphate mixture.
  • Both the dose proportional and the dose similar had suitable pharmaceutical properties in terms of disintegration times, tablet hardness and correct proportion of lisinopril to chlorthalidone throughout the tablet run.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des formulations de posologie fixe d'un inhibiteur d'enzyme de conversion de l'angiotensine (ACE), de préférence du Lisinopril et un diurétique, de préférence de la Chlorthalidone, dans le même support pharmaceutiquement acceptable, par exemple un comprimé, une capsule ou une suspension orale, ainsi que des procédés de traitement de l'hypertension par l'administration de la formulation de posologie fixe de Lisinopril et de Chlorthalidone à un patient en ayant besoin.
PCT/US2015/023193 2014-04-01 2015-03-27 Formulations de posologie fixe d'inhibiteur d'enzyme de conversion de l'angiotensine (ace) et de chlorthalidone diurétique WO2015153379A1 (fr)

Applications Claiming Priority (2)

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US201461973776P 2014-04-01 2014-04-01
US61/973,776 2014-04-01

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WO2015153379A1 true WO2015153379A1 (fr) 2015-10-08

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017077425A1 (fr) * 2015-11-07 2017-05-11 Ftf Pharma Private Limited Solution orale à base d'inhibiteurs d'ace

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245787B1 (en) * 1995-03-16 2001-06-12 Pfizer Inc. Composition containing amlodipine or a pharmaceutically acceptable salt thereof, and an ACE inhibitor
US20040254176A1 (en) * 2002-05-17 2004-12-16 Grigorieff Melissa Lynn Combination of an ace inhibitor, a calcium channel blocker and a diuretic
US20070004792A1 (en) * 2005-07-01 2007-01-04 Lawrence Solomon Method of treating hypertension with a very low dose of chlorthalidone
US20070237815A1 (en) * 2006-04-06 2007-10-11 Lawrence Solomon Dosage forms and methods comprising amlodipine and chlorthalidone

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4808413A (en) * 1987-04-28 1989-02-28 E. R. Squibb & Sons, Inc. Pharmaceutical compositions in the form of beadlets and method
US6458769B1 (en) * 2001-06-25 2002-10-01 Astrazeneca Ab Amorphous compound
EP1948136A1 (fr) * 2005-11-07 2008-07-30 King Pharmaceuticals Research and Development, Inc. Compositions de ramipril stabilise en combinaison avec un autre agent actif
US20070116756A1 (en) * 2005-11-23 2007-05-24 Dr. Reddy's Laboratories Limited Stable pharmaceutical compositions

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6245787B1 (en) * 1995-03-16 2001-06-12 Pfizer Inc. Composition containing amlodipine or a pharmaceutically acceptable salt thereof, and an ACE inhibitor
US20040254176A1 (en) * 2002-05-17 2004-12-16 Grigorieff Melissa Lynn Combination of an ace inhibitor, a calcium channel blocker and a diuretic
US20070004792A1 (en) * 2005-07-01 2007-01-04 Lawrence Solomon Method of treating hypertension with a very low dose of chlorthalidone
US20070237815A1 (en) * 2006-04-06 2007-10-11 Lawrence Solomon Dosage forms and methods comprising amlodipine and chlorthalidone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
S KOLNIK ET AL., COMBINATION ANTIHYPERTENSIVE DRUGS: RECOMMENDATIONS FOR USE. AM FAM PHYSICIAN, vol. 61, no. 10, 15 May 2000 (2000-05-15), pages 3049 - 3056 *

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